SUMMARY Centenarians, people that live to 100 years of age, are remarkably protected from dementias, despite their advanced age. Understanding factors that protect centenarians from Alzheimer?s disease (AD) may provide new leads for successful treatment. Our parent grant application investigates the role of SIRT6 protein in epigenome stability, genome maintenance and suppression of LINE1 (L1) transposable elements. Importantly, SIRT6 deficient mice show neurodegeneration, and SIRT6 levels are reduced in patients with AD. We discovered that L1s are activated during aging, especially in the brain, and the cytoplasmic DNA copies of L1s trigger type I interferon response. We hypothesize that the neuroinflammation induced by L1 activity contributes to the development of AD. Recently, a coding variant of SIRT6 has been identified in centenarians. Our preliminary data shows that the centenarian variant of SIRT6 has higher mono-ADP-ribosylation activity, enhances DNA repair, and provides stronger suppression of L1 transposable elements. Our recent study also demonstrates that long-lived mammalian species possess more active SIRT6 protein. Our hypothesis is that SIRT6 from long-lived animals or long-lived humans confers protection against AD by promoting genome and epigenome stability, and by reducing neuroinflammation. Bowhead whale is the longest-lived mammal with the maximum lifespan of 211 years. Here we propose to examine whether overexpressing bowhead whale SIRT6, or human centenarian SIRT6 variants in AD model mice delays the disease progression. These experiments will serve as a proof of principle that activating SIRT6 may be used as therapeutic strategy against AD.